Splitting and lumping in the nosology of XLMR

Abstract

Although it is assumed that genes that influence cognitive function are ubiquitous in the human genome, to date, more such genes have been found on the X chromosome than on any other comparable segment of the autosomes. This is in large measure because of the power of hemizygosity in exposing mutations of X-linked genes in males. Clinical manifestations, mapping of gene loci by linkage analysis or chromosome rearrangements, and gene identification by positional cloning or mutational analysis of candidate genes have permitted extensive lumping and splitting within the large and heterogeneous category of X-linked mental retardation (XLMR). Approximately 130 XLMR syndromes have been identified, 25 gene loci have been mapped and cloned, and 55 other loci have been mapped but not cloned. Well-recognized syndromes (e.g., Fragile X and Coffin-Lowry syndromes) and syndromes represented by only a single family (e.g., Arena and monoamine oxidase-A syndromes) are among these more or less well-defined entities. In addition, more than 75 families with nonsyndromal XLMR have been regionally mapped and 7 causative genes have been identified.

ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal

“…An estimated 10% of mental retardation is believed to be attributed to genes on the X chromosome 1 , 2. While studies vary in their measurement tools and intelligence quotient (IQ) classification, mental retardation is estimated to affect up to 3% of the population with societal cost estimates exceeding those for stroke, heart disease and cancer combined 3 , 4.…”

The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene

“…1 Notable among the XLMR syndromes so linked are those associated with mutations in L1 cell-adhesion molecule , aristaless-related homoeobox, X-linked nuclear protein, filamin A and polyglutamine tract binding protein 1 genes. [1][2][3][4][5][6][7] In some instances, the linked syndromes have overlapping clinical manifestations (eg, L1 cell-adhesion molecule gene mutations in MASA (mental retardation, aphasia, shuffling gait, adducted thumbs) syndrome, X-linked hydrocephaly and spastic paraplegia type 1), and in other instances the linked entities exhibit rather disparate clinical presentations (eg, filamin A gene mutations in periventricular nodular heterotopia, Melnick-Needles syndrome and otopalatodigital syndrome). 1 6 7 A recurrent mutation (c.2881CRT, p.R961W) in exon 21 of the mediator subunit 12 gene (MED12, also known as HOPA and TRAP230) has been found in the original family with FG syndrome and in five other families with compatible clinical findings.…”

X chromosome cDNA microarray screening identifies a functional PLP2 promoter polymorphism enriched in patients with X-linked mental retardation

“…X-linked mental retardation (XLMR) is a genetically heterogeneous group of disorders caused by defects of genes on the X chromosome (Ropers and Hamel 2005). Collectively, XLMR disorders are more common than fragile X syndrome, occurring in 1.66/1000 males in the general population (0.22/1000 males) (Turner et al 1996;Stevenson 2000). Numerous studies have established a 25%-30% male excess in the mentally retarded population and a substantial fraction of the male excess is thought to be due to defects of genes on the X chromosome (Wing 1971;Herbst and Miller 1980;Hane et al 1996).…”